Neurobiology of Suicide: Childhood Adversity, Neuroinflammation and Genomics

摘要-项目1 童年逆境与成年抑郁症（MDD），攻击性特征和 自杀项目1的总体目标是定义自杀的生物学表型，并评估其对自杀的贡献。 报告的童年（16岁之前）逆境。在MDD自杀者中，我们发现儿童期不良反应的比例更高， 事件这种关系的生物学基础大多是未知的，但最近的研究，包括我们的发现， 前额叶皮质（PFC）变薄，海马（HC）体积变小， 脑源性神经营养因子，表明糖皮质激素过量和营养作用受损是压力的结果，并有助于 自杀风险压力和自杀也与前额皮质的细胞减少和树突萎缩有关 (PFC)和海马（HC）。较薄的PFC和较小的HC体积可能构成生物风险因素 压力相关的精神病理学我们假设这种神经生物学表型可能是由 神经炎症、环境和表观遗传效应。在新的孔蒂中心，我们的目标是确定在 PFC和HC，炎症细胞因子是否增加，神经元，神经胶质细胞或两者是否表达这些 炎症标志物，以及这些标志物的存在是否与神经元的变化有关。 5组（每组n=15）年龄和性别匹配的MDD自杀者的数量或形态， 有和没有报告的童年逆境（15岁之前）的非精神病对照组和10名非自杀MDD， 都是通过心理解剖和大脑毒理学我们建议测量：1）62个标记的 在背侧PFC（dPFC），ACC和HC的炎性小体;我们将估计神经元和胶质细胞的总数， HC以及dPFC和ACC中的神经元和胶质细胞密度，神经元和胶质细胞用选择性双标记 从炎性小体测定中鉴定的细胞因子; 2）我们将计数HC中的小胶质细胞的数量（在 前、中、后水平）和dPFC和ACC中小胶质细胞的密度，使用小胶质细胞特异性 标记物;和3）确定树突长度和分支作为神经元形态的指标。 探索性的目标是：1）分离抑郁症与自杀或逆境对神经元和胶质细胞的影响 比较自杀和非自杀MDD组选择的炎症标志物的表达; 2）比较 来自脑和血液的细胞因子;死后脑中并通过PET测量的TSPO水平;皮质厚度和 死后脑中的HC体积，并通过MRI在体内测量。拟议的研究将提供证据， CA和自杀是否与神经炎症反应有关。 !

SUMMARY- PROJECT 1 Childhood adversity is associated with greater risk for adulthood depression (MDD), aggressive traits and suicide. The overall goal of Project 1 is to define a biological phenotype for suicide and assess the contribution of reported childhood (before age 16) adversity. In MDD suicides, we find a higher rate of childhood adverse events. The biological basis of this relationship is mostly unknown, but recent studies, including finds from our previous Conte Center of thinner prefrontal cortex (PFC) and smaller hippocampus (HC) volume and reduced BDNF, suggest glucocorticoid excess and impaired trophic effect is a consequence of stress and contributes to suicide risk. Stress and suicide are also associated with fewer cells and dendritic shrinkage in prefrontal cortex (PFC) and hippocampus (HC). The thinner PFC and smaller HC volume may constitute a biological risk factor for stress-related psychopathology. We hypothesize that this neurobiological phenotype may result from neuroinflammation, environment and epigenetic effects. In the new Conte Center, we aim to determine in the PFC and HC, whether inflammatory cytokines are increased, whether neurons, glia or both express those inflammatory markers, and whether the presence of those markers is associated with changes in neuron number or morphology in 5 groups (n=15 per group) of age- and sex-matched MDD suicides and nonpsychiatric controls with and without reported childhood adversity (before 15y) and 10 non suicide MDDs, all with psychological autopsy and brain toxicology. We propose to measure: 1) 62 markers of the inflammasome in the dorsal PFC (dPFC), ACC and HC; we will estimate total number of neurons and glia in HC and neuronal and glial density in the dPFC and ACC, with neurons and glia double-labeled with select cytokines identified from the inflammasome assay; 2) we will count the number of microglia in the HC (at anterior, mid- and posterior levels) and the density of microglia in dPFC and ACC using microglia specific markers; and 3) Determine the dendrite length and branching as indices of neuron morphology. Exploratory aims will: 1) separate the effect of MDD from that of suicide or adversity on neuron and glia expression of select inflammatory markers comparing the suicide and non-suicide MDD groups; 2) compare cytokines from brain and blood; TSPO level in postmortem brain and measured by PET; cortical thickness and HC volume in postmortem brain and measured in vivo by MRI. The proposed studies will provide evidence whether CA and suicide are associated with a neuroinflammatory response. !